@article {642436, title = {Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.}, journal = {Nat Med}, year = {2016}, month = {2016 Feb 1}, abstract = {Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.}, issn = {1546-170X}, doi = {10.1038/nm.4040}, author = {Hata, Aaron N and Niederst, Matthew J and Archibald, Hannah L and Gomez-Caraballo, Maria and Siddiqui, Faria M and Mulvey, Hillary E and Maruvka, Yosef E and Ji, Fei and Bhang, Hyo-Eun C and Krishnamurthy Radhakrishna, Viveksagar and Siravegna, Giulia and Hu, Haichuan and Raoof, Sana and Lockerman, Elizabeth and Kalsy, Anuj and Lee, Dana and Keating, Celina L and Ruddy, David A and Damon, Leah J and Crystal, Adam S and Costa, Carlotta and Piotrowska, Zofia and Bardelli, Alberto and Iafrate, Anthony J and Sadreyev, Ruslan I and Stegmeier, Frank and Getz, Gad and Sequist, Lecia V and Faber, Anthony C and Engelman, Jeffrey A} }